Vulnerable populations at risk of acquiring HIV include racial minorities. While African Americans make up13% of the US population, they account for about half of the HIV/AIDS new diagnoses. Since 2000, several reports have suggested that oral HPV growths are increasing in people with HIV/AIDS on HAART, and that this is more prevalent in vulnerable populations, such as African Americans than Whites. The central hypothesis of this Program Project is that alterations in innate defense mechanisms determine susceptibility to oral complications following HIV infection. Human beta defensins (hBDs) have been the focus of our group's research in HIV for more than seven years. We have discovered that oral epithelial cell-derived beta defensins can: 1) be induced by HIV; 2) inhibit the ability of the virus to infect immunocompetent cells; and 3) interact with specific chemokine and toll-like receptors resulting in regulation of adaptive immune cells. Moreover, chronic HIV infection and/or highly active antiretroviral therapy (HAART) predisposes the oral mucosae to both cellular and innate immune impairment. Interestingly, amongst the repertoire of innate immune molecules, hBDs are unique, as copy number variations have only been reported for the beta defensin gene cluster; possibly explaining the interpersonal variability in hBD expression levels. Our multidisciplinary program is synergistic through the direct collaboration and interaction of our faculty and core facilities that will support the projects. Investigators in Project 1 and Project 2 will cooperatively design, produce, and share altered forms of beta defensin molecules that will be utilized in structure/function studies in both projects that explore defensin interactions with chemokine and toll-like receptors. Investigators from Projects 1 and 3 will utilize expertise in immunology and dermatology to design and implement studies that explore the cross-talk between epithelial cells and antigen presenting cells. Projects 3 and 4 will share tissue isolated from oral warts and other oral mucosal complication associated with HIV to examine their protein and genomic profiles. Thus, these projects are highly integrated on both a theoretical and collaborative basis and involve a multidisciplinary approach that includes expertise in defensin biology, structural chemistry, HIV immunology, dermatology and genetics. Finally, projects will be supported by the Proteomics and Biostatistics Core (Core B), and information gathered through the Program Project will be examined so that the sum of the data may generate overarching conclusions regarding our central hypothesis. All the data will be subjected to rigorous scientific scrutiny through meetings between the PIs and an External Advisory Panel that will be organized through the Administrative Core (Core A).